Half-life antipsychotics

Mechanism of Action An antipsychotic agent that provides partial agonist activity at dopamine and serotonin (S-HTj ) receptors and antagonist activity at serotonin (5-HTja) receptors. Therapeutic Effect Diminishes schizophrenic behavior. Pharmacokinetics Well absorbed through the GI tract. Protein binding 99% (primarily albumin). Reaches steady levels in 2 wk. Metabolized in the liver. Eliminated primarily in feces and, to a lesser extent, in urine. Not removed by hemodialysis. Half-life 75 hr. 

This agent has a broad spectrum of activity encompassing several neurotransmitter systems. In this light, clozapine is similar to such phenothiazines as CPZ and thioridazine (519). It is also subject to a hepatic first-pass effect, which produces metabolites with low or unknown pharmacological activity. It has an elimination half-life ranging from 6 to 33 hours and a volume of distribution (V 5 l /kg) lower than most other antipsychotics. This last quality indicates less drug is sequestered in tissue sites. Plasma levels of the parent compound at or above 350 ng/mL may be associated with a better clinical response ( 66, 520). Plasma levels are lower in men than women, especially male smokers (329). 

Typical doses of clonazepam have been in the range of 2 to 16 mg/day given on a once or twice per day schedule due to its longer half-life. A major advantage of this anticonvulsant is its relative lack of adverse effects and freedom from laboratory monitoring in comparison with CBZ and VPA. Clonazepam may be more useful when combined with lithium or CBZ rather than as a specific antimanic agent, perhaps supplanting the need for antipsychotics. In this sense, it can be viewed as a behavioral suppressor, rather than a true mood stabilizer (121). 

Buspirone may be an effective anxiolytic in the elderly patient and less likely than BZDs to produce excessive sedation ( 352, 353, 354 and 355). Dizziness, however, may be a problem. Zolpidem or zaleplon, particularly in lower doses (i.e., 2.5 to 5.0 mg at bedtime) may be viable alternatives ( 356). The elimination half-life of these two agents is approximately 3 hours in the elderly. Although it has sleep-enhancing properties similar to BZD hypnotics, it is less likely to alter sleep architecture. Whereas antidepressants and b -blockers may be useful alternatives in younger patients, no data document their effectiveness for anxiety in elderly patients ( 307). Although antipsychotics may be helpful in reducing severe agitation, their side effect profile makes them unsuitable for use in subjective anxiety states ( 300, 307). 

In the management of anxiety, the cumulative effects of longer half-life BZDs often result in excessive sleepiness, apathetic states, and confusion (with or without paradoxical agitation). Thus, short- and intermediate-acting agents such as oxazepam, lorazepam, and alprazolam are preferable. Lower doses (e g., 0.5 to 1.0 mg of lorazepam 0.25 to 0.5 mg of alprazolam) are preferable. Agents with very short half-lives, such as midazolam and triazolam, are not well tolerated, especially in those with more severe neurocognitive disruption. In this context, low-dose antipsychotics were found more effective than lorazepam in the treatment of AIDS-related delirium (495). 

Haloperidol is used as an antipsychotic and occasionally for control of acute agitation in the intensive care unit. It is can also be useful in the treatment of phencyclidine abuse. It produces a cataleptic state with little drowsiness and has minimal effects on blood pressure and respiration. It is a long-acting drug with a half-life of about 18 hours. It is available in oral and injectable preparations. In large doses extrapyramidal side effects may occur. 

Amoxapine is also rapidly absorbed with protein binding of about 85%. The half-life is variable, and the drug is often given in divided doses. Amoxapine undergoes extensive hepatic metabolism. One of the active metabolites, 7-hydroxyamoxapine, is a potent D2 blocker and is associated with antipsychotic effects. Maprotiline is similarly well... 

Very short half-life, buf some pafienfs may only require once daily dosing Other patients may do better with 3 or 4 divided doses daily Patients receiving atypical antipsychotics may occasionally require a top up of a conventional antipsychotic to control aggression or violent behavior... 

Trade names Abilify (Bristol-Myers Squibb) Abilitat Indications Schizophrenia Category Antipsychotic Mood stabilizer Half-life 75-94 hours... 

Trade names Apo-Carbamazepine Atreol Carbatrol Epitol (Teva) Foxsalepsin Kodapan Lexin Mazepine Sirtal Tegretol (Novartis) Tegretol XR Teril Timonil Indications Epilepsy, pain or trigeminal neuralgia Category Anticonvulsant Antipsychotic Mood stabilizer Half-life 18-55 hours... 

Indications Psychosis, manic-depressive disorders Category Antipsychotic, phenothiazine Muscarinic antagonist Half-life initial 2 hours terminal 30 hours Clinically important, potentially hazardous interactions with alcohol, antihistamines, arsenic, chlorpheniramine, dofetilide, epinephrine, evening primrose, guanethidine, mivacurium, quinolones, sparfloxacin... 

Indications Tranquilizer and antiemetic in surgical procedures Category Antipsychotic Butyrophenone Half-life 2.3 hours... 

Trade names Anatensol Apo-Fluphenazine Dapatum D25 Dapotum D Fludecate Modecate Moditen Prolixin Indications Psychoses Category Antipsychotic, phenothiazine Half-life 84-96 hours... 

Trade names Dozic Duraperidol Haldol (Ortho-McNeil) Haloper Peridol Seranace Serenace Indications Psychoses, Tourette s disorder Category Antipsychotic, butyrophenone Half-life 20 hours... 

Trade names Desconex Loxapac Loxitane (Watson) Indications Psychoses Category Antipsychotic, tricyclic Half-life 12-19 hours (terminal)... 

Indications Schizophrenia Category Antipsychotic Half-life 1.5 hours... 

Indications Psychotic disorders Category Antipsychotic Muscarinic antagonist Half-life 21-54 hours... 

Trade names Frenal Neurap Orap (Gate) Pimodac Indications Tourette s syndrome, schizophrenia Category Antipsychotic Half-life 50 hours... 

Category Antipsychotic, phenothiazine Muscarinic antagonist Half-life 23 hours... 

Trade names Liranol Prazine Protactyl Savamine Talofen Indications Psychotic disorders, schizophrenia Category Antipsychotic, phenothiazine Half-life 24 hours... 

Trade names Aldazine Apo-Thioridazine Calmaril Dazine Mellaril (Novartis) Melleril Ridazin Thinin Thioril Indications Psychotic disorders Category Antipsychotic, phenothiazine Half-life 21-25 hours... 

Trade names Calmazine Domilium Flupazine Fluzine Nerolet Psyrazine Sedizine Stelazine TFP Indications Psychoses, anxiety Category Antipsychotic, phenothiazine Half-life 10-20 hours... 

Category Antipsychotic Histamine HI receptor antagonist Half-life N/A... 

Indications Seizures, migraine Category Anticonvulsant Antipsychotic Half-life 6-16 hours... 

I Sedation and Cognition. Sedation must be recognized as an antipsychotic side effect and not as an indication of therapeutic effect. It occurs more frequently with antipsychotics with antihistaminic properties. Chlorpromazine, thioridazine, mesoridazine, clozapine, olanzapine, and quetiapine are most frequently implicated. Administration of most or all of the daily dosage at bedtime (depending on the drug half-life) can decrease daytime sedation and in some patients eliminate the need for hypnotic agents. Sedation occurs early in treatment... 

The chronic administration of molecules, which have a short biological half-life and cannot be given orally, presents a difficult challenge to formulators. One strategy which might be considered is the development of a sustained-release intramuscular or subcutaneous injection. Other non-parenteral options could include the inhalation or intranasal route, both of which have their own unique challenges. Sustained-release parenteral formulations might also be required in circumstances where patient compliance is likely to be poor. This consideration has led to the development of some antipsychotics and contraceptives as sustained-release injections. Table 9.6 lists some of the sustained-release parenteral products which are available on the U.S. market and their respective formulations. The typical approaches used in the formulation of sustained-release parenterals are summarised in this section. 

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